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Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a heterogeneous and clinically important phenotype in which improved risk stratification tools are needed, and mitochondrial dysfunction may contribute to its pathophysiology. We aimed to evaluate the association between serum Mitofusin-2 (MFN2) levels and cardiac biomarkers and hematologic inflammatory indices in MINOCA, and to determine their potential diagnostic and prognostic value. A total of 30 MINOCA patients presenting with acute coronary syndrome (ACS) and non-obstructive coronary arteries on urgent coronary angiography, and 30 controls without an ACS presentation who underwent elective coronary angiography and had normal coronary arteries were included. Serum MFN2 was measured by ELISA at day 0 in both groups and repeated at day 3 in the MINOCA group, together with routine biochemistry, complete blood count-derived inflammatory indices and angiographic scores. Left ventricular ejection fraction (LVEF) was significantly lower, and both Gensini and SYNTAX scores were significantly higher compared with controls (p&#x2009;<&#x2009;0.05). At admission, no significant differences were observed in inflammatory indices between the control and MINOCA-0 groups, whereas by day 3 in MINOCA, neutrophil-to-lymphocyte ratio (NLR), C-reactive protein/albumin ratio (CAR), pan-immune-inflammation value (PIV), systemic inflammatory index (SII), monocyte-to-lymphocyte ratio (MLR), and systemic inflammation response index (SIRI) increased significantly and prognostic nutritional index (PNI), Glascow prognostic score (GPS), and lymphocyte-to-monocyte ratio (LMR) decreased significantly (p&#x2009;<&#x2009;0.05). Serum MFN2 levels increased significantly on day 3 compared with day 0 within the MINOCA group (p&#x2009;<&#x2009;0.0001). MFN2 showed a strong negative correlation with aspartate aminotransferase (AST) in both groups at day 0, and additionally demonstrated inverse associations with lymphocyte count in MINOCA (day 0-3). In Receiver Operating Characteristic (ROC) analyses, MFN2 did not show significant predictive/discriminative value for hospitalization for MINOCA either at presentation or when day 0 and day 3 MINOCA measurements were combined. MFN2 demonstrates a delayed rise during early hospitalization in MINOCA but lacks diagnostic discrimination at presentation, supporting its evaluation as a longitudinal (rather than acute) biomarker candidate.

Background/Objectives: Regular physical exercise conditioning attenuates nociceptive responses. However, it remains unclear whether physical exercise performed before local inflammation exerts prolonged preventive effects. This study determined whether treadmill run (TR) preconditioning produces sustained preventive effects on craniofacial nociception and associated brain responses following persistent craniofacial inflammation. Methods: Male C57BL/6J mice were assigned to sedentary or TR groups. Daily TR conditioning was performed for 10 days before masseter muscle injection of complete Freund's adjuvant (CFA) on Day 0. Craniofacial-pain- and related anxiety-like behaviors were determined by the orofacial formalin, elevated plus maze, and open-field tests before and 3 (CFA3) or 7 (CFA7) days after CFA injection. Brain responses in the amygdala, insular cortex, hippocampal CA1, and primary motor cortex were assessed using multiple epigenetic- and neural-activity-related markers. Results: Under sedentary conditions, both CFA3 and CFA7 groups showed increased pain- and anxiety-like behaviors and elevated expression of epigenetic- and neural-activity-related markers in most brain regions. TR preconditioning attenuated these behavioral responses even three and seven days after TR cessation and altered the expression of epigenetic markers in several brain regions, although the direction of change varied by region and time point. TR preconditioning consistently reduced the expression of neural activity markers in most brain areas in both the CFA3 and CFA7 groups, with a few exceptions. Conclusions: TR preconditioning exerted prolonged preventive effects on craniofacial-pain-like behaviors and associated brain responses following craniofacial inflammation.

Background: Acne vulgaris affects up to 80% of individuals aged 11-30 years and frequently results in permanent scarring with significant psychosocial impact. This prospective single-arm case series evaluated the safety and high-frequency ultrasound-assessed morphological changes in a combined protocol integrating subcision, PEGDE-crosslinked hyaluronic acid supplemented with calcium hydroxyapatite (CaHA), and fractional 1470 nm diode laser therapy in patients with facial atrophic acne scars. Methods: Twenty patients (aged 18-42 years, Fitzpatrick phototypes I-II) with moderate-to-severe atrophic acne scars underwent subcision of fibrotic adhesions using a 22G cannula combined with a single subcutaneous injection of 2 mL PEGDE-crosslinked hyaluronic acid with CaHA microparticles on day 0, followed by two sessions of fractional 1470 nm diode laser therapy on days 7 and 28. Scar depth and diameter were assessed using high-frequency ultrasound (48 MHz) at baseline and on days 28, 49, 77, and 139. Results: All participants completed the protocol without serious adverse events. High-frequency ultrasound demonstrated progressive reductions in mean scar depth (from 0.35 to 0.05 mm; -86%) and scar diameter (from 4.27 to 1.06 mm; -75%) by day 139, with reductions continuing beyond the active treatment phase. In linear mixed-effects models accounting for within-patient clustering of the two lesions assessed per participant, the reductions in both depth and diameter were statistically significant at every follow-up timepoint relative to baseline (all p < 0.001). These ultrasound findings were not corroborated by a control group, blinded assessment, validated clinical grading, or patient-reported outcomes. Conclusions: In this single-arm case series, the combined subcision, PEGDE-crosslinked HA-CaHA filler, and fractional 1470 nm diode laser protocol was well tolerated and associated with progressive, sustained reductions in high-frequency ultrasound-measured scar depth and diameter. As an uncontrolled, unblinded study without validated clinical grading or patient-reported outcomes, these findings are preliminary and require confirmation in larger, controlled trials.

This study qualitatively explored psychological change processes as described by participants and therapists within a phase 2a clinical trial evaluating the safety, tolerability, and preliminary efficacy of a single dose of intranasal 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT; BPL-003) administered alongside psychological support and manualised cognitive behavioural therapy (CBT) for relapse prevention in alcohol use disorder (AUD). Embedded qualitative sub-study within an open-label, phase 2a, single-dose (Day 0) clinical trial with 12-week follow-up (Day 84 endpoint). Semi-structured interviews were conducted remotely with participants at Day 1 post-dose and end-of-study (Day 84). Therapists were interviewed once to triangulate participant accounts and explore perceived change processes in the context of psychological support and CBT. One drug and alcohol service and one research facility in London, UK (29 March 2023-2 July 2024). Ten participants (8 men, 2 women) with moderate to severe AUD and six therapists who worked on the study. Interviews with participants followed a topic guide covering alcohol use history and motivations; expectations, intentions and preparation; acute dosing-day experiences; perceived psychological and behavioural changes; and the perceived role of support and relapse-prevention CBT. Therapists were interviewed to provide a complementary professional viewpoint on the changes and role of support. All interviews were audio-recorded, transcribed verbatim, and analysed using an interpretative phenomenological perspective supported by iterative categorisation. Immediately after dosing, participants commonly described the experience using metaphors of a "reset", "cleansing", or "rebirth", often accompanied by emotional catharsis and rapid shifts in self-perception. They reported increased clarity regarding their relationship with alcohol, enhanced emotional openness, and improved self-compassion and interpersonal connectedness. At the 12-week follow-up, participants who maintained abstinence (n&#x2009;=&#x2009;5) described the psychedelic experience as a pivotal turning point, facilitating sustained reappraisals of identity, values, and patterns of alcohol use. They also reported greater mindfulness, cognitive flexibility, and emotional acceptance, coupled with enhanced relationship quality, better sleep, increased energy, and overall well-being. Participants who resumed moderated drinking (n&#x2009;=&#x2009;2) reported similarly increased self-awareness, reduced compulsivity, and greater emotional regulation. Therapist accounts closely corroborated these participant narratives, highlighting observed shifts in psychological flexibility, emotional openness, and adaptive behavioural responses. Therapists also noted that the psychedelic experience enabled rapid relaxation and revision of maladaptive core beliefs and promoted resilience and acceptance, even in participants with initially challenging experiences. Participant and therapist accounts indicate that a single dose of 5-methoxy-N,N-dimethyltryptamine, when embedded in a relapse-prevention cognitive behavioural therapy programme, can support meaningful shifts in self-appraisal, emotional regulation, and behavioural patterns associated with alcohol consumption.

Mother's own milk (MOM) is considered the optimal nutriton for preterm infants. When MOM is insufficient, donor human milk (DHM) is the preferred alternative for very preterm infants, but processing is known to affect the composition of the bioactive components. This pilot study aimed to describe the analytical methods and investigate levels of bioactive components in preterm and term MOM according to lactation stages and compare with DHM: 1) total MFGM and MFGM protein levels, 2) proteins related to MFGM and EV: BA46, CD81 and xanthine oxidase (XOD) levels and 3) lipid content and composition. Colostrum, transitional and mature milks were collected from healthy mothers, who gave birth to either term (n = 10) or very preterm (n = 10) infants, at day 0-4, 7-14 and 28-45 after delivery, respectively. Thirteen pooled DHM samples were also included. MFGM quantification, Western blotting and lipidomics were used for analysis. Preterm samples were compared with term samples according to lactation stage and all MOM samples were compared with DHM. MFGM level was significantly lower in preterm colostrum compared with term colostrum (15.5 &#xb1; 1.1 vs. 18.1 &#xb1; 4.2, p-value = 0.02). No differences between preterm and term milk were found in later lactation stages (all p-value >0.05). DHM had significantly lower levels of MFGM compared with preterm and term MOM (p-value <0.05). BA46, CD81 and XOD levels did not differ between preterm and term milk at any lactation stage (all p-value >0.05). Preterm and term milk contained higher amounts of BA46, CD81 and XOD compared to DHM. There were no major differences in lipid class composition of preterm and term milk. To highlight, preterm milk contained significantly higher amounts of sphingomyelin compared to DHM at all lactation stages (all p-value <0.05), whereas term milk did not differ significantly from DHM (all p-value >0.05). With these preliminary results we conclude that preterm and term MOM were largely comparable in MFGM, associated proteins and lipid composition across lactation stages. In contrast, DHM contained lower levels of MFGM and associated proteins, explaining its lower bioactive potential for very preterm infants.

Mosquito-borne arboviral diseases such as dengue and chikungunya have continuously been a major global public health concern. Introducing the intracellular bacterial endosymbiont Wolbachia into mosquito populations has been proven to reduce dengue virus transmission, and its broader efficacy against other arboviruses has also been investigated. Several Wolbachia strains have been successfully propagated in insect cell lines, highlighting the utility of in vitro systems for studying microbial-host interactions under controlled conditions. This study investigated the initial establishment and replication kinetics of a flea-derived Wolbachia strain (wCfe), which was originally isolated from Malaysian Ctenocephalides felis and maintained in the Ixodes scapularis tick-derived cell line (IDE8), and then transferred into an Aedes albopictus-derived cell line (C6/36). The wCfe strain was semi-purified from IDE8 cultures and inoculated into C6/36 cells in 24-well plates. Replication dynamics were monitored by quantitative real-time PCR targeting the Wolbachia pipientis 16S rRNA gene. Following infection, a lag phase was observed at day 0 to 5 days post-infection (d.p.i.), followed by exponential growth from 6 d.p.i. after which Wolbachia levels remained relatively stable until the end of the observation period at 12 d.p.i. Overall, a 25.30-fold increase in Wolbachia density was detected relative to 0 d.p.i. Across replicates, the estimated generation time of wCfe in C6/36 cells ranged from 1.7 to 2.5 days. These results demonstrate successful initial establishment and replication of the flea-derived Wolbachia strain in the Aedes mosquito cell line. However, longer-term in vivo studies will be necessary to determine the persistence of wCfe infection in C6/36 cells and within the mosquito host.

AIM: To investigate the effects of sodium nitrite on spinal cord development in early-stage chick embryos. MATERIAL and METHODS: Sixty specific-pathogen-free fertile Leghorn-type eggs at Day 0 of incubation were used. Group 1 (control) received saline, Group 2 (low-dose) was administered 0.0042 mg of sodium nitrite, and Group 3 (high-dose) received 0.0084 mg. Embryonic disks were microscopically examined after 72 hours of incubation. RESULTS: In the control group, the surface ectoderm was intact, the neural tube was properly closed, and the neuroepithelium, basement membrane, somites, and notochord exhibited normal morphology. Neural tube defects were identified in seven embryos in the low-dose group and nine embryos in the high-dose group. Statistical analysis revealed that both sodium nitrite-exposed groups exhibited a significantly higher incidence of neural tube defects compared with the control group (p < 0.05). However, no statistically significant difference was observed between the low- and high-dose groups. CONCLUSION: Exposure to low and high doses of sodium nitrite induced neural tube defects in chick embryos, suggesting potential embryotoxic effects.

Background: High-risk (HR) prostate cancer has a propensity for local and distant progression with ultimate death, mandating aggressive locoregional and systemic treatment approaches to maximize oncologic outcomes. Although brachytherapy (BT) with supplemental therapies has demonstrated favorable biochemical and quality of life outcomes, improvements in overall survival have been hampered by an excessive incidence of non- prostate cancer deaths. In this HR study, we report on biochemical failure (BF), prostate cancer-specific mortality (PCSM), overall mortality (OM) and patterns of death with recommendations for the mitigation of non-prostate cancer deaths. Materials and Methods: From April 1995 to November 2018, 577 consecutive HR patients were treated with LDR BT (97.9% Pd-103). Patients were stratified into three age cohorts: &#x2264; 59, 60-69 and &#x2265;70 years. The BT prescription dose was prescribed to the prostate gland with generous peri-prostatic margins and the proximal 10mm of the seminal vesicles. 94.6% received supplemental EBRT (45-50.4 Gy) and 63.3% received androgen deprivation therapy (ADT) (median duration 12 months). Post-implant CT-based dosimetry was performed on day 0. BF was defined as a PSA > 0.40 ng/mL after nadir. The cause of death was determined for each patient. Patients with metastatic prostate cancer or non-metastatic castrate resistant prostate cancer who died of any cause were classified as dead of prostate cancer. All other deaths were attributed to the immediate cause. Multiple clinical, pathologic and treatment were evaluated for impact on patient outcomes. Results: Of the patients, 87.5% (median follow-up 8.9 years) presented with a single HR factor. The day 0 D90 was 122.5%. Overall, the 15-year BF, PCSM and OM were 12.4%, 5.6% and 51.7%. When stratified by age, there was no significant difference in BF or PCSM. The median post- treatment PSA in biochemically controlled patients was <0.01 ng/mL. In all three cohorts, OM increased linearly for the first 10 years and then approximately doubled from years 10 to 15. Moreover, 239 patients died: 10.9% due to prostate cancer, 38.1% from cardiovascular (CV) disease and 28.4% from other malignancies (to include one rectal and three bladder cancers). In MVA, BF was most closely related to percent positive biopsies (p < 0.001, SHR 1.018), PCSM to Gleason score (p = 0.004, SHR 2.884) and percent positive biopsies (p = 0.005, SHR 1.021) and OM to age (p < 0.001, HR 1.075) and tobacco (p < 0.001, HR 2.374). Conclusions: Despite high cancer control rates, overall survival was limited by a preponderance of CV and non-prostate cancer deaths, which were 6 times more likely than prostate cancer deaths. The implementation of a comprehensive multidisciplinary survivorship program will be essential to impact longevity in this patient population.

Background/Objectives: Benzydamine hydrochloride (B-HCl) is a non-steroidal anti-inflammatory agent with antimicrobial properties that may be beneficial in oral biofilm control. The aim of this study was to evaluate the effect of a 0.15% B-HCl mouthrinse on dental plaque accumulation and gingival inflammation under short-term conditions of restricted mechanical oral hygiene. Methods: Fifty periodontally healthy female subjects (aged 16-27 years) were randomly assigned (1:1) to receive either a 0.15% B-HCl mouthrinse or a placebo. Following professional prophylaxis, subjects rinsed with 15 mL twice daily for 30 s and refrained from all other oral hygiene procedures for 3 days. Full-Mouth Plaque Score (FMPS) was the primary outcome, and Full-Mouth Bleeding Score (FMBS) was the secondary outcome, recorded at baseline (Day 0) and Day 3. This study was conducted in accordance with CONSORT guidelines. Results: All subjects (n = 50) completed the study. FMPS increased significantly in both groups (p < 0.001). However, plaque accumulation at Day 3 was significantly lower in the B-HCl group compared with placebo (47.9% vs. 73.8%, p < 0.001), representing an absolute reduction of 25.9% and a relative reduction of 35.1%. No statistically significant differences were observed between groups in FMBS at Day 3 (p = 0.180). Conclusions: A 0.15% B-HCl mouthrinse reduced dental plaque accumulation compared with placebo during a 3-day period of restricted mechanical oral hygiene (mean difference: 25.9%; 95% CI: 16.1% to 35.7%). Given the short study duration, the anti-inflammatory properties of B-HCl could not be adequately evaluated. Longer-term studies are needed to determine whether B-HCl provides clinically meaningful benefits as an adjunct to mechanical oral hygiene. Trial registration: ClinicalTrials.gov (Identifier: NCT07565766).

This was a pre-clinical study designed to investigate the potential of combining hyperthermia with checkpoint inhibitors. C3H mammary carcinomas, grown in the right rear foot of CDF1 mice, were treated when tumors reached 200&#x2009;mm3. Hyperthermia (39.5-42.5&#x2009;&#xb0;C for 30-120&#x2009;min) was applied following immersion of the tumor bearing leg into a circulating water bath. The checkpoint inhibitors were anti-CTLA-4/PD-1/PD-L1 antibodies injected intraperitoneally (4 x 10&#x2009;mg/kg). Tumor growth was monitored daily and the treatment endpoint was TGT5 (time for tumors to regrow to 5 times treatment volume). None of the antibodies alone affected TGT5 when compared to controls. However, while neither the anti-PD-1 nor anti-PD-L1 antibodies influenced heat response, an enhanced effect was found with the anti-CTLA-4 antibody. This was most apparent when tumors were heated once at 42.5&#x2009;&#xb0;C for 1-hour on day 0 and the antibody administered on days 1, 4, 8 and 11 or 1, 2, 3 and 4 after heating. However, the responses were heterogenous with some animals treated with heat and anti-CTLA-4 showing an increase in TGT5 compared to heat alone, while others showed no change. Mechanistic studies of tumor blood perfusion and infiltrating lymphocytes in tissue sections showed a substantial decrease reaching a nadir 1-3&#x2009;days after heating, with recovery by 7-10&#x2009;days. Under specific conditions, there appeared to be an enhanced anti-tumor effect with the hyperthermia-checkpoint inhibitor combination, but these effects were often sporadic. Mechanisms for the interaction between heat and the anti-CTLA-4 antibody remain unclear.

Acute pancreatitis (AP) is a common gastrointestinal emergency with unpredictable progression and high mortality in severe cases. Traditional prognostic scores such as APACHE II, BISAP, and SOFA are limited by complexity and delayed applicability. Red blood cell distribution width (RDW), a simple and universally available biomarker, has emerged as a potential prognostic indicator. This study assessed the predictive value of RDW for short- and long-term mortality in critically ill patients with AP. We conducted a retrospective cohort study using the MIMIC-IV database. Adult patients with a primary diagnosis of AP were included, with exclusions for repeat admissions, ICU stay <48&#xa0;h, hematologic malignancy, or end-stage renal disease. Baseline RDW at ICU admission was the primary exposure. Primary outcomes were 28-day and 90-day all-cause mortality. Associations were evaluated using Kaplan-Meier analysis, Cox regression, restricted cubic splines, and subgroup analyses. Incremental prognostic performance was assessed with AUC, net reclassification index (NRI), and decision curve analysis (DCA). A total of 450 patients met inclusion criteria. The overall 28-day and 90-day mortality rates were 8.7% and 12.0%, respectively. Patients with elevated RDW (>14.5%) had significantly higher mortality at both 28&#xa0;days (13.4% vs. 4.3%, p&#xa0;<&#xa0;0.001) and 90&#xa0;days (18.7% vs. 6.5%, p&#xa0;<&#xa0;0.001). In fully adjusted Cox models, RDW remained an independent predictor of mortality (28-day: HR&#xa0;=&#xa0;1.31, 95% CI: 1.15-1.50; 90-day: HR&#xa0;=&#xa0;1.28, 95% CI: 1.16-1.41). RDW demonstrated strong discriminatory ability (AUC: 0.837 for 28-day, 0.807 for 90-day mortality). Incorporating RDW into a multivariable baseline model including demographics, comorbidities, and laboratory indicators of organ dysfunction improved predictive accuracy (&#x394;AUC +0.06; NRI&#xa0;=&#xa0;0.21, p&#xa0;<&#xa0;0.001). RDW is a low-cost, widely accessible biomarker that independently predicts short- and long-term mortality in critically ill patients with AP. Its inclusion in conventional prognostic models may enhance risk stratification and may support earlier, tailored clinical decision-making. Prospective multicenter validation is warranted.

To evaluate the feasibility of same-day (postoperative day 0; POD0) physical therapy (PT) following lumbar fusion and to identify factors associated with failure to participate. This retrospective study analyzed prospectively collected data from patients undergoing single-level posterior spinal fusion (PSF), with or without anterior (ALIF) or lateral (LLIF) interbody fusion, between January and December 2024 at a single institution. A standardized POD0 PT protocol was implemented for eligible patients. Patients were categorized into two groups: successful POD0 PT (ambulatory on POD0) and unable to participate. Demographic and surgical variables were compared between groups. Reasons for inability to participate were recorded and categorized. Among 129 patients in whom POD0 PT was attempted, 84 (65%) successfully participated, while 45 (35%) were unable. There were no significant differences in age, sex, BMI, ASA class, operative time, estimated blood loss, or surgical approach between groups. Patients who successfully completed POD0 PT had a significantly shorter hospital length of stay compared to those who did not (3.4&#xa0;&#xb1;&#xa0;1.6 vs 5.8&#xa0;&#xb1;&#xa0;2.9&#xa0;days, P&#xa0;<&#xa0;0.001), with no differences in complication rates, discharge disposition, emergency department visits, or reoperation rates. The most common barriers to POD0 PT were postoperative pain, medical issues (e.g., orthostatic hypotension, nausea, dizziness), and anesthesia-related somnolence. Less common factors included postoperative restrictions and logistical issues such as brace availability. POD0 PT following lumbar fusion is feasible in the majority of patients and is associated with a shorter hospital stay without increased complications. Failure to participate was not associated with the baseline patient or surgical characteristics evaluated in this study. Instead, the most common barriers were postoperative pain, transient medical issues, and anesthesia-related somnolence, suggesting that optimization of modifiable perioperative factors may improve the implementation of POD0 PT.

Gradual changes in muscle resistance after ischemic stroke offer precious insights into the time-course development of spastic hypertonia, but quantitative data about temporal changes in muscle tension are insufficient, particularly about changes in muscle properties in post-stroke animal models. In male Sprague-Dawley rats, changes in the motor function, muscle tension, and spastic muscle structure over a 20-day period after permanent middle cerebral artery occlusion (MCAO) were examined using behavioral tests, electrophysiological recordings, and muscle fiber staining. Motor function evaluated by gait analysis and rotarod test performance were impaired from day 0 to day 10. Muscle tension assessed by Modified Modified Ashworth Scale (MMAS) dropped immediately after MCAO, began to rise on day 3, peaked on day 10, and then decreased somewhat, yet remained relatively high throughout the 20-day observation period. These alterations in muscle tension were also verified by H-reflex recording. On days 10 and 20 postoperatively, the percentage of type I muscle fibers in MCAO group was higher than in sham-operated animals. Our results verified a progressive increase in muscle tension and motor dysfunction on days 3-10 after cerebral ischemia, while changes in structural properties of spastic muscles also contributed to hypertonia. The findings may contribute to better understanding of the recovery process in spastic hypertonia quantitatively in animal model after stroke, and are useful for developing new therapeutic approaches.

Higher coffee intake has been associated with lower risk of type 2 diabetes (T2D), but the underlying biological pathways remain incompletely understood. To examine associations of coffee intake with insulin sensitivity, adiposity, and T2D risk, and assess whether coffee intake modifies associations between pathway-specific genetic susceptibility and incident T2D. Cross-sectional analyses among 806 participants without T2D in the VITamin D and OmegA-3 TriaL (VITAL) clinical sub-cohort, who underwent repeated dietary assessment, clinical phenotyping, and dual-energy X-ray absorptiometry imaging at baseline and year-2. Prospective analyses among 333,053 UK Biobank participants without T2D at baseline who had dietary and genetic data and were followed for a median of 13.3 years. Coffee intake assessed by food frequency questionnaires. In UK Biobank, 12 pathway-specific polygenic scores (pPS) representing distinct T2D pathophysiological mechanisms were evaluated. The primary outcomes, in VITAL, were HbA1c, oral glucose tolerance test-derived measures of glucose response and insulin sensitivity, &#x3b2;-cell function, and overall, truncal, and visceral adiposity; in UK Biobank, was incident T2D. In VITAL, higher coffee intake was associated with higher insulin sensitivity (standardized &#x3b2; per cup/day, 0.046; P = .004) and lower visceral adipose tissue mass (&#x3b2;, -0.047; P = .006), after adjusting for demographic, lifestyle, and clinical factors, including body mass index. In UK Biobank, higher coffee intake was associated with lower T2D incidence (hazard ratio per cup/day, 0.96; 95% CI, 0.95-0.97), lower triglyceride-to-HDL cholesterol ratio (&#x3b2;,-0.01; P = 2.51 &#xd7; 10^-19), and lower visceral adipose tissue mass (&#x3b2;, -0.01; P = 4.28 &#xd7; 10^-9). Associations of 3 pPS related to insulin resistance and fat distribution with incident T2D were attenuated among participants consuming higher amount of coffee than among non-consumers (P for interaction < .0043). Higher coffee intake was associated with greater insulin sensitivity, lower visceral adiposity, and lower risk of T2D. Together with the attenuation of associations between pathway-specific genetic susceptibility and T2D risk among higher coffee consumers, these findings suggest that insulin resistance and visceral adiposity-related pathways may contribute to the association between coffee intake and T2D risk. Question: Is coffee intake associated with specific insulin sensitivity and adiposity markers, and type 2 diabetes risk, and does it modify associations between pathway-specific genetic susceptibility and type 2 diabetes?Findings: In analyses repeated dietary, clinical, and imaging phenotyping in 806 VITAL participants and prospective data from 333,053 UK Biobank participants, higher coffee intake was associated with greater insulin sensitivity, lower visceral adiposity, and lower type 2 diabetes risk. Higher coffee intake also attenuated associations of three pathway-specific polygenic scores related to insulin resistance and fat distribution with type 2 diabetes risk.Meaning: These findings suggest that pathways related to insulin sensitivity and visceral adiposity may contribute to the associations between coffee intake and lower type 2 diabetes risk.

Peripheral nerve blockade is a common analgesic technique in anterior cruciate ligament (ACL) reconstruction. The comparative opioid-sparing and functional outcomes of continuous femoral nerve block (CFNB) versus continuous adductor canal block (CACB) are unclear. In this single-center, double-blind, prospective, superiority randomized controlled trial, 60 adults undergoing ACL reconstruction were randomized to receive either CFNB or CACB. All patients received a 20&#x2009;mL loading dose of 0.5% ropivacaine and were discharged with a 0.2% ropivacaine infusion (5&#x2009;mL/hour basal, 5&#x2009;mL demand bolus, 30&#x2009;min lockout). The primary outcome was average numeric rating scale (NRS) pain scores analyzed using a linear mixed-effects repeated-measures model over 48 hours. Secondary outcomes included cumulative morphine milligram equivalents (MME), continuous passive motion (CPM) usage, CPM compliance, and Quality of Recovery-15 (QoR-15) scores. 57 patients completed the study (CFNB n=28; CACB n=29). Mixed-effects repeated-measures analysis of average NRS pain scores at 24 and 48 hours showed no significant difference between CFNB and CACB. The estimated overall treatment effect for CFNB versus CACB was -0.31 NRS points (p=0.58, 95% CI -1.39 to 0.77), with no significant treatment-by-time interaction (p=0.97). Current NRS pain scores were lower for CFNB on postoperative day 0 (POD0) (p=0.02, 95%&#x2009;CI 6.44&#xd7;10-6 to 2.00). In an exploratory analysis, fewer CFNB patients required more than 50 MME during the 48-hour follow-up period compared with CACB (CFNB: 5/28 vs CACB: 13/29; p=0.045, 95%&#x2009;CI 0.08 to 0.93). The absolute risk difference was 0.27 (95% CI -0.08 to 0.54). There were no differences in CPM use or compliance, bolus volume, or QoR-15. CFNB was not superior to CACB on the primary pain outcome over 48 hours. In secondary analysis, CFNB catheters were associated with lower immediate postoperative pain. In exploratory analyses, fewer patients required more than 50 MME over 48 hours. This finding is hypothesis-generating and requires confirmation in an adequately powered trial. There were no differences in quality of recovery or CPM compliance. Whether any opioid-related differences between techniques outweigh concerns about motor blockade warrants further investigation. NCT03208478.

Measurement of faecal haemoglobin (f-Hb) using the faecal immunochemical test (FIT) in population screening for colorectal cancer (CRC) has reduced cancer-related incidence and mortality. However, temperature-induced f-Hb degradation can decrease FIT accuracy. This study assessed the f-Hb preservation capacity of a new FIT Hb-stabilising buffer at different temperatures and durations. Fresh whole faecal samples from individuals with active colorectal bleeding were used for collection of samples using the OC-Sensor FIT (EIKEN CHEMICAL CO. LTD, Japan) containing either the standard (SOC3) or new formulation (SOC4) buffer. Pooled faeces-buffer mixtures (n&#x2009;=&#x2009;29) were divided into aliquots for incubation at 4&#xb0;C, 23&#xb0;C, 35&#xb0;C, 45&#xb0;C, and 50&#xb0;C and analysed for f-Hb concentration at days 0, 3, 7, 10, 14, 21, and 28. Relative f-Hb (percentage change of day 0) in both buffer types was compared between temperatures at each timepoint. Generalised linear modelling identified variables influencing f-Hb degradation. SOC3 exhibited significant f-Hb decline from day 10 at 23&#xb0;C and from day 3 at all higher temperatures assessed (p&#x2009;<&#x2009;0.05). In contrast, f-Hb concentrations remained stable within SOC4 for up to 28&#x2009;days at 23&#xb0;C, with reductions observed after 7, 7, and 14&#x2009;days at 50&#xb0;C, 45&#xb0;C, and 35&#xb0;C, respectively (p&#x2009;<&#x2009;0.05). Higher temperatures and longer storage duration significantly decreased f-Hb concentration, while SOC4 demonstrated superior f-Hb preservation relative to SOC3 (generalised linear model estimate&#x2009;=&#x2009;15.4, p&#x2009;<&#x2009;0.001). The SOC4 FIT buffer improves f-Hb stability compared with the current formulation and may improve CRC screening accuracy, particularly in high-temperature environments.

Skeletal and synovial joint development involves distinct skeletal stem/progenitor populations. However, in neural crest-derived temporomandibular joint (TMJ), skeletal stem/progenitor lineage dynamics and ossification programs remain poorly defined. Here, we performed single-cell RNA sequencing (scRNA-seq) on mouse mandibular cartilage at embryonic day 16.5 (E16.5), postnatal day 0 (P0), and 13 weeks to construct a high-resolution atlas of skeletal stem/progenitor populations. At embryonic and postnatal stages, the outer perichondrium contained Lgr5+Pthlh+ cells expressing Dlx5, consistent with an intramembranous ossification-associated program. In contrast, a previously uncharacterized Crabp1+ subpopulation within the inner perichondrium expressed Nrg1, Lsamp, Tac1, and Igfbp5, consistent with an early chondrogenic-associated transcriptional state. These results suggest spatially distinct ossification-associated programs and reveal the transcriptional regulation underlying TMJ development. Our findings provide a model for understanding neural crest-derived TMJ skeletal stem/progenitor cell regulation and may inform future studies of TMJ cartilage biology and regeneration strategies within this specialized tissue.

Due to their underdeveloped thermoregulatory system, neonates are at increased risk of morbidity and mortality from hot and cold temperatures. Our study aimed to analyse the effects of environmental temperature on overall, very early, early and late neonatal acute mortality in five East African countries using the Demographic and Health Surveys (DHS) data. We obtained neonatal mortality data from the DHS conducted between 2016 and 2022, capturing births and deaths occurring between 2011 and 2022. Our outcomes were (1) overall neonatal mortality (days 0-27), (2) very early (day 0); (3) early (days 1-6) and (4) late neonatal mortality (days 7-27). Daily mean temperature was constructed from ERA5-Land and assigned at the household level. We used a time-stratified case-crossover design with distributed lag non-linear models (0-6-day lag) to estimate odds of mortality with exposure to the 5th and 95th temperature percentiles (vs the median). Country-level estimates were generated and then pooled to assess the overall association. A total of 1373 neonatal deaths were included, over 80% of which occurred within the first 6&#x2009;days of life. The association between ambient temperature and neonatal mortality was heterogeneous. In pooled analysis, the 95th and 5th percentiles were associated with increased and decreased mortality odds respectively, although estimates were imprecise. In Uganda, there was strong evidence of association between high ambient temperature (95th percentile) and overall neonatal mortality (OR=3.54; 95%&#x2009;CI 1.73 to 7.28) as well as early neonatal mortality (OR=3.75; 1.70 to 8.28), while odds of very early neonatal mortality increased with exposure to low temperatures (5th percentile) (OR=5.65; 1.89 to 16.69). There was no strong evidence of association in other countries. Temperature-related neonatal mortality risk differs across East African countries. Other factors may play a significant role. Future research should consider the effects of environmental temperature on neonatal mortality across different climate zones.

Emerging evidence suggests that uremic toxins (UTs) may exacerbate organ dysfunction in septic-shock-associated AKI. However, the dynamic changes in serum concentrations of these solutes and their specific prognostic implications remain largely unexplored. This prospective study enrolled 114 patients with septic shock and AKI, alongside 15 non-AKI septic shock controls. We measured serum levels of seven UTs (indoxyl sulfate, indole-3-acetic acid, para-cresyl sulfate, para-cresyl glucuronide, hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), and trimethylamine N-oxide ) daily from Day 0 to Day 6. We analysed toxin kinetics and their relationship with 28-day mortality and the time to successful liberation from vasopressor and invasive mechanical ventilation, using joint modelling for longitudinal and survival data. Upon inclusion, 30% of patients had Stage 1, 30% Stage 2, and 40% Stage 3 AKI. Except for CMPF, all toxins accumulated significantly compared to controls and remained significantly higher in severe AKI throughout the observation period (p<0.001). Indoxyl sulfate showed the strongest longitudinal correlations with serum creatinine (r=0.67, p<0.001). Daily kidney replacement therapy (KRT) status was associated with lower levels of most UTs, with the notable exceptions of indoxyl sulfate (unaffected) and hippuric acid (positively associated). Forty-four patients (39%) died within 28 days. After adjusting for baseline SAPS II and nonrenal SOFA scores, UT trajectories were not significantly associated with 28-day mortality or the time to successful liberation from organ support. Changes in serum UT concentrations correlated with the severity and trajectory of AKI during septic shock, and exhibited variable clearance during KRT, but were not independently associated with 28-day mortality or organ support dependence.